HRP20140481T1 - Substituted imidazo[1,2-b]pyridazine compounds as trk kinase inhibitors - Google Patents

Substituted imidazo[1,2-b]pyridazine compounds as trk kinase inhibitors Download PDF

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HRP20140481T1
HRP20140481T1 HRP20140481AT HRP20140481T HRP20140481T1 HR P20140481 T1 HRP20140481 T1 HR P20140481T1 HR P20140481A T HRP20140481A T HR P20140481AT HR P20140481 T HRP20140481 T HR P20140481T HR P20140481 T1 HRP20140481 T1 HR P20140481T1
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Steven W. Andrews
Julia Haas
Yutong Jiang
Gan Zhang
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Array Biopharma, Inc.
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Claims (23)

1. Spoj opće formule I [image] , ili njegova farmaceutski prihvatljiva sol, naznačen time što: R1 je H ili (1-6C alkil); R2 je NRbRc, (1-4C)alkil, (1-4C)fluoralkil, CF3, (1-4C)hidroksialkil, -(1-4C alkil)hetAr1, -(1-4C alkil)NH(1-4C alkil), hetAr2, hetCyc1, hetCyc2, fenil, izborno supstituiran s NHSO2(1-4C alkilom), ili (3-6C)cikloalkil, izborno supstituiran s (1-4C alkilom), CN, OH, CF3, CO2(1-4C alkilom) ili CO2H; Rb je H ili (1-6C alkil); Rc je H, (1-4C)alkil, (1-4C)hidroksialkil, hetAr3 ili fenil, gdje je navedeni fenil izborno supstituiran s jednim ili više supstituenata, koje se neovisno bira između halogena, CN, CF3 i -O(1-4C alkila), ili NRbRc tvori 4-eročlani heterociklički prsten, koji u prstenu ima atom dušika, gdje je navedeni heterociklički prsten izborno supstituiran s jednim ili više supstituenata, koje se neovisno bira između halogena, OH, (1-4C alkila), (1-4 C)alkoksi, -OC(=O)(1-4C alkila), NH2, -NHC(=O)O(1-4C alkila) i (1-4C)hidroksialkila, ili NRbRc tvori 5-6-eročlani heterociklički prsten, koji u prstenu ima heteroatom koji je dušik i izborno u prstenu ima drugi heteroatom ili skupinu, koje se bira između N, O i SO2, gdje je heterociklički prsten izborno supstituiran s jednim ili više supstituenata, koje se neovisno bira između OH, halogena, CF3, (1-4C)alkila, CO2(1-4C alkila), CO2H, NH2, NHC(=O)O(1-4C alkila) i okso, ili NRbRc tvori 7-8-eročlani premošteni heterociklički prsten, koji u prstenu ima 1-2 atoma dušika i izborno je supstituiran s CO2(1-4C alkilom); hetAr1 je 5-eročlani heteroarilni prsten, koji u prstenu ima 1-3 atoma dušika; hetAr2 je 5-6-eročlani heteroarilni prsten, koji u prstenu ima najmanje jedan atom dušika i izborno u prstenu ima drugi heteroatom, kojeg se neovisno bira između N i S, gdje je navedeni heteroarilni prsten izborno supstituiran s jednim ili više supstituenata, koji se neovisno biraju između (1-4C alkila), halogena, -(1-4 C)alkoksi i NH(1-4C alkila); hetCyc1 je preko ugljika vezani 4-6-eročlani azaciklički prsten, izborno supstituiran s jednim ili više supstituenata, koje se neovisno bira između (1-4C alkila), CO2H i CO2(1-4C alkila); hetCyc2 je piridinonski ili piridazinonski prsten, supstituiran sa supstituentom koji se bira između (1-4C)alkila; hetAr3 je 5-6-eročlani heteroarilni prsten, koji u prstenu ima 1-2 heteroatoma, koji se neovisno biraju između N i O, i izborno je supstituiran s jednim ili više supstituenata, koji se neovisno biraju između (1-4C)alkila; Y je fenilni prsten, izborno supstituiran s jednim ili više supstituenata, koji se neovisno biraju između halogena, (1-4C)alkoksi, CF3 i CHF2, ili 5-6-eročlani heteroarilni prsten, koji u prstenu ima heteroatom biran između N i S; X je ništa, -CH2-, -CH2CH2-, -CH2O- ili -CH2NRd-; Rd je H ili (1-4C alkil); R3 je H ili (1-4C alkil); svaki R4 se neovisno bira između halogena, (1-4C)alkila, OH, (1-4 C)alkoksi, NH2, NH(1-4C alkila) i CH2OH; i n je 0, 1, 2, 3, 4, 5 ili 6.1. Compound of general formula I [image] , or its pharmaceutically acceptable salt, characterized in that: R 1 is H or (1-6C alkyl); R2 is NRbRc, (1-4C)alkyl, (1-4C)fluoroalkyl, CF3, (1-4C)hydroxyalkyl, -(1-4C alkyl)hetAr1, -(1-4C alkyl)NH(1-4C alkyl) , hetAr2, hetCyc1, hetCyc2, phenyl, optionally substituted with NHSO2(1-4C alkyl), or (3-6C)cycloalkyl, optionally substituted with (1-4C alkyl), CN, OH, CF3, CO2(1-4C alkyl ) or CO2H; Rb is H or (1-6C alkyl); Rc is H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr3 or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CF3 and -O(1- 4C alkyl), or NRbRc forms a 4-membered heterocyclic ring, which has a nitrogen atom in the ring, where said heterocyclic ring is optionally substituted with one or more substituents, which are independently chosen from halogen, OH, (1-4C alkyl), (1-4 C )Alkoxy, -OC(=O)(1-4C alkyl), NH2, -NHC(=O)O(1-4C alkyl) and (1-4C)hydroxyalkyl, or NRbRc forms a 5-6-membered heterocyclic ring, which has a nitrogen heteroatom in the ring and optionally another heteroatom or group in the ring, which is selected from N, O and SO2, where the heterocyclic ring is optionally substituted with one or more substituents , which is independently chosen from OH, halogen, CF3, (1-4C)alkyl, CO2(1-4C alkyl), CO2H, NH2, NHC(=O)O(1-4C alkyl) and oxo, or NRbRc forms a 7-8-membered bridged heterocyclic ring, which has 1-2 nitrogen atoms in the ring and is optionally substituted with CO2(1-4C alkyl); hetAr1 is a 5-membered heteroaryl ring, which has 1-3 nitrogen atoms in the ring; hetAr2 is a 5-6-membered heteroaryl ring, which has at least one nitrogen atom in the ring and optionally has another heteroatom in the ring, which is independently chosen from N and S, where the said heteroaryl ring is optionally substituted with one or more substituents, which independently choose from (1-4C alkyl), halogen, -(1-4 C) alkoxy and NH(1-4C alkyl); hetCyc1 is a carbon-bonded 4-6-membered azacyclic ring, optionally substituted with one or more substituents, which are independently chosen from (1-4C alkyl), CO2H and CO2(1-4C alkyl); hetCyc2 is a pyridinone or pyridazinone ring, substituted with a substituent selected from (1-4C)alkyl; hetAr3 is a 5-6-membered heteroaryl ring, which has 1-2 heteroatoms in the ring, which are independently selected from N and O, and is optionally substituted with one or more substituents, which are independently selected from (1-4C)alkyl; Y is a phenyl ring, optionally substituted with one or more substituents, which are independently selected from halogen, (1-4C) alkoxy, CF3 and CHF2, or a 5-6-membered heteroaryl ring, which has a heteroatom selected from N and S in the ring ; X is none, -CH2-, -CH2CH2-, -CH2O- or -CH2NRd-; Rd is H or (1-4C alkyl); R3 is H or (1-4C alkyl); each R 4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4C)alkoxy, NH 2 , NH(1-4C alkyl) and CH 2 OH; and n is 0, 1, 2, 3, 4, 5 or 6. 2. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je R2 NRbRc.2. A compound according to claim 1, characterized in that R2 is NRbRc. 3. Spoj u skladu s patentnim zahtjevom 1 ili 2, naznačen time što: NRbRc tvori 4-eročlani heterociklički prsten, koji u prstenu ima atom dušika, izborno supstituiran s jednim ili više supstituenata, koje se neovisno bira između halogena, OH, (1-4C alkila), (1-4 C)alkoksi, -OC(=O)(1-4C alkila), NH2, -NHC(=O)O(1-4C alkila) i (1-4C)hidroksialkila, ili NRbRc tvori 5-6-eročlani heterociklički prsten, koji u prstenu ima heteroatom koji je dušik i izborno u prstenu ima drugi heteroatom ili skupinu, koji se biraju između N, O i SO2, gdje je heterociklički prsten izborno supstituiran s jednim ili više supstituenata, koje se neovisno bira između OH, halogena, CF3, (1-4C)alkila, CO2(1-4C alkila), CO2H, NH2, NHC(=O)O(1-4C alkila) i okso, ili NRbRc tvori 7-8-eročlani premošteni heterociklički prsten, koji u prstenu ima 1-2 atoma dušika i izborno je supstituiran s CO2(1-4C alkilom).3. A compound according to claim 1 or 2, characterized in that: NRbRc forms a 4-membered heterocyclic ring, which has a nitrogen atom in the ring, optionally substituted with one or more substituents, which are independently chosen from halogen, OH, (1-4C alkyl), (1-4 C) alkoxy, -OC( =O)(1-4C alkyl), NH2, -NHC(=O)O(1-4C alkyl) and (1-4C)hydroxyalkyl, or NRbRc forms a 5-6-membered heterocyclic ring, which has a nitrogen heteroatom in the ring and optionally another heteroatom or group in the ring, which are selected from N, O and SO2, where the heterocyclic ring is optionally substituted with one or more substituents , which is independently chosen from OH, halogen, CF3, (1-4C)alkyl, CO2(1-4C alkyl), CO2H, NH2, NHC(=O)O(1-4C alkyl) and oxo, or NRbRc forms a 7-8 membered bridged heterocyclic ring, which has 1-2 nitrogen atoms in the ring and is optionally substituted with CO2(1-4C alkyl). 4. Spoj u skladu s patentnim zahtjevom 1 ili 2, naznačen time što: Rb je H ili (1-6C alkil); i Rc je H, (1-4C)alkil, (1-4C)hidroksialkil, hetAr3 ili fenil, gdje je navedeni fenil izborno supstituiran s jednim ili više supstituenata, koji se neovisno biraju između halogena, CN, CF3 i -O(1-4C alkila).4. A compound according to claim 1 or 2, characterized in that: Rb is H or (1-6C alkyl); and Rc is H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr3 or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CF3 and -O(1- 4C alkyl). 5. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je R2 (1-4C)alkil, (1-4C)fluorakil, CF3, -(1-4C alkil)hetAr1 ili -(1-4C alkil)NH(1-4C alkil).5. A compound according to claim 1, characterized in that R2 is (1-4C)alkyl, (1-4C)fluoroalkyl, CF3, -(1-4C alkyl)hetAr1 or -(1-4C alkyl)NH(1 -4C alkyl). 6. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-5, naznačen time što je X ništa, -CH2- ili -CH2CH2-.6. A compound according to any one of claims 1-5, characterized in that X is nothing, -CH2- or -CH2CH2-. 7. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-6, naznačen time što je Y fenilni prsten, izborno supstituiran s jednim ili više supstituenata, koji se neovisno biraju između halogena, (1-4C)akoksi, CF3 i CHF2.7. A compound according to any one of claims 1-6, characterized in that Y is a phenyl ring, optionally substituted with one or more substituents, which are independently selected from halogen, (1-4C) oxy, CF3 and CHF2. 8. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-7, naznačen time što Y ima apsolutnu konfiguraciju prikazanu na Slici Ia: [image] .8. A compound according to any one of claims 1-7, characterized in that Y has the absolute configuration shown in Figure Ia: [image] . 9. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-8, naznačen time što je R3 H.9. A compound according to any one of claims 1-8, characterized in that R3 is H. 10. Spoj u skladu s patentnim zahtjevom 1, naznačen time što: R1 je H ili (1-6C alkil); R2 je NRbRc; NRbRc tvori 4-eročlani heterociklički prsten, koji u prstenu ima atom dušika, gdje je navedeni heterociklički prsten izborno supstituiran s jednim ili više supstituenata, koji se neovisno bira između halogena, OH, (1-4C alkila), (1-4 C)alkoksi, -OC(=O)(1-4C alkila), NH2, -NHC(=O)O(1-4C alkila) i (1-4C)hidroksialkila, ili NRbRc tvori 5-6-eročlani heterociklički prsten, koji u prstenu ima heteroatom koji je dušik i izborno u prstenu ima drugi heteroatom ili skupinu, koji se bira između N, O i SO2, gdje je heterociklički prsten izborno supstituiran s jednim ili više supstituenata, koji se neovisno biraju između OH, halogena, CF3, (1-4C)alkila, CO2(1-4C alkila), CO2H, NH2, NHC(=O)O(1-4C alkila) i okso; Y je fenil, izborno supstituiran s jednim ili više supstituenata, koji se neovisno biraju između halogena, (1-4C)alkoksi, CF3 i CHF2; X je ništa, -CH2- ili -CH2CH2-; R3 je H ili (1-4C alkil); svaki R4 se neovisno bira između halogena, (1-4C)alkila, OH, (1-4 C)alkoksi, NH2, NH(1-4C alkila) i CH2OH; i n je 0, 1 ili 2.10. A compound according to claim 1, characterized in that: R 1 is H or (1-6C alkyl); R2 is NRbRc; NRbRc forms a 4-membered heterocyclic ring, which has a nitrogen atom in the ring, where said heterocyclic ring is optionally substituted with one or more substituents, which are independently chosen from halogen, OH, (1-4C alkyl), (1-4 C) Alkoxy, -OC(=O)(1-4C alkyl), NH2, -NHC(=O)O(1-4C alkyl) and (1-4C)hydroxyalkyl, or NRbRc forms a 5-6 membered heterocyclic ring, which has a nitrogen heteroatom in the ring and optionally another heteroatom or group in the ring, which is selected from N, O and SO2, where the heterocyclic ring is optionally substituted with one or more substituents , which are independently selected from OH, halogen, CF3, (1-4C)alkyl, CO2(1-4C alkyl), CO2H, NH2, NHC(=O)O(1-4C alkyl) and oxo; Y is phenyl, optionally substituted with one or more substituents independently selected from halogen, (1-4C) alkoxy, CF 3 and CHF 2 ; X is none, -CH2- or -CH2CH2-; R3 is H or (1-4C alkyl); each R 4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4C)alkoxy, NH 2 , NH(1-4C alkyl) and CH 2 OH; and n is 0, 1 or 2. 11. Spoj u skladu s patentnim zahtjevom 10, naznačen time što: R1 je H ili (1-6C alkil); R2 je NRbRc; NRbRc tvori 5-6-eročlani heterociklički prsten, koji u prstenu ima heteroatom koji je dušik i izborno u prstenu ima drugi heteroatom ili skupinu, koji se bira između N, O i SO2, gdje je heterociklički prsten izborno supstituiran s jednim ili više supstituenata, koji se neovisno biraju između OH, halogena, CF3, (1-4C)alkila, CO2(1-4C alkila), CO2H, NH2, NHC(=O)O(1-4C alkila) i okso; Y je fenil, izborno supstituiran s jednim ili više supstituenata, koji se neovisno biraju između halogena, (1-4C)alkoksi, CF3 i CHF2; X je -CH2-; R3 je H ili (1-4C alkil); svaki R4 se neovisno bira između halogena, (1-4C)alkila, OH, (1-4 C)alkoksi, NH2, NH(1-4C alkila) i CH2OH; i n je 0, 1 ili 2.11. A compound according to claim 10, characterized in that: R 1 is H or (1-6C alkyl); R2 is NRbRc; NRbRc forms a 5-6-membered heterocyclic ring, which has a nitrogen heteroatom in the ring and optionally another heteroatom or group in the ring, which is selected from N, O and SO2, where the heterocyclic ring is optionally substituted with one or more substituents, which are independently selected from OH, halogen, CF3, (1-4C)alkyl, CO2(1-4C alkyl), CO2H, NH2, NHC(=O)O(1-4C alkyl) and oxo; Y is phenyl, optionally substituted with one or more substituents independently selected from halogen, (1-4C) alkoxy, CF 3 and CHF 2 ; X is -CH2-; R3 is H or (1-4C alkyl); each R 4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4C)alkoxy, NH 2 , NH(1-4C alkyl) and CH 2 OH; and n is 0, 1 or 2. 12. Spoj u skladu s patentnim zahtjevom 11, naznačen time što je heterociklički prsten kojeg tvori NRbRc izborno supstituiran s jednim ili dva supstituenta, koji se neovisno biraju između OH, F, NH2, CO2H, CO2Et, NHCO2C(CH3)3, CF3, metila, etila, izopropila, CO2C(CH3)3 i okso.12. A compound according to patent claim 11, characterized in that the heterocyclic ring formed by NRbRc is optionally substituted with one or two substituents, which are independently chosen from OH, F, NH2, CO2H, CO2Et, NHCO2C(CH3)3, CF3, methyl, ethyl, isopropyl, CO2C(CH3)3 and oxo. 13. Spoj u skladu s patentnim zahtjevom 12, naznačen time što je Y fenil izborno supstituiran s jednim ili više atoma halogena.13. A compound according to claim 12, characterized in that Y phenyl is optionally substituted with one or more halogen atoms. 14. Spoj u skladu s patentnim zahtjevom 10, naznačen time što R1 je H ili (1-6C alkil); R2 je NRbRc; NRbRc tvori 4-eročlani heterociklički prsten, koji u prstenu ima atom dušika, gdje je navedeni prsten izborno supstituiran s jednim ili više supstituenata, koji se neovisno biraju između halogena, OH, (1-4C alkila), (1-4 C)alkoksi, -OC(=O)(1-4C alkila), NH2, -NHC(=O)O(1-4C alkil) i (1-4C)hidroksialkil; Y je fenil, izborno supstituiran s jednim ili više supstituenata, koji se neovisno biraju između halogena, (1-4C)alkoksi, CF3 i CHF2; X je -CH2-; R3 je H ili (1-4C alkil); svaki R4 se neovisno bira između halogena, (1-4C)alkila, OH, (1-4 C)alkoksi, NH2, NH(1-4C alkila) i CH2OH; i n je 0, 1 ili 2.14. A compound according to claim 10, characterized in that R 1 is H or (1-6C alkyl); R2 is NRbRc; NRbRc forms a 4-membered heterocyclic ring, which has a nitrogen atom in the ring, where said ring is optionally substituted with one or more substituents, which are independently chosen from halogen, OH, (1-4C alkyl), (1-4 C) alkoxy , -OC(=O)(1-4C alkyl), NH2, -NHC(=O)O(1-4C alkyl) and (1-4C)hydroxyalkyl; Y is phenyl, optionally substituted with one or more substituents independently selected from halogen, (1-4C) alkoxy, CF 3 and CHF 2 ; X is -CH2-; R3 is H or (1-4C alkyl); each R 4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4C)alkoxy, NH 2 , NH(1-4C alkyl) and CH 2 OH; and n is 0, 1 or 2. 15. Spoj u skladu s patentnim zahtjevom 14, naznačen time što je heterociklički prsten kojeg tvori NRbRc izborno supstituiran s jednim ili dva supstituenta, koje se neovisno bira između F, OH, metila, OMe, OC(=O)C(CH3)2, NH2, -NHC(=)OC(CH3)3 i CH2OH.15. A compound according to claim 14, characterized in that the heterocyclic ring formed by NRbRc is optionally substituted with one or two substituents, which are independently chosen from F, OH, methyl, OMe, OC(=O)C(CH3)2 , NH2, -NHC(=)OC(CH3)3 and CH2OH. 16. Spoj u skladu s patentnim zahtjevom 15, naznačen time što je Y fenil izborno supstituiran s jednim ili više atoma halogena.16. A compound according to claim 15, characterized in that Y phenyl is optionally substituted with one or more halogen atoms. 17. Spoj u skladu s bilo kojim od patentnih zahtjeva 10-16, naznačen time što je n nula ili jedan.17. A compound according to any one of claims 10-16, characterized in that n is zero or one. 18. Spoj u skladu s patentnim zahtjevom 17, naznačen time što je R3 vodik.18. A compound according to claim 17, characterized in that R3 is hydrogen. 19. Spoj u skladu s patentnim zahtjevom 18, naznačen time što je R1 vodik.19. A compound according to claim 18, characterized in that R1 is hydrogen. 20. Farmaceutski pripravak, naznačen time što sadrži spoj Formule I u skladu s bilo kojim od patentnih zahtjeva 1 do 19, ili njegova farmaceutski prihvatljiva sol, i farmaceutski prihvatljiv razrjeđivač ili podlogu.20. A pharmaceutical preparation, characterized in that it contains a compound of Formula I according to any of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 21. Spoj Formule I u skladu s bilo kojim od patentnih zahtjeva 1 do 19, ili njegova farmaceutski prihvatljiva sol, naznačen time što je namijenjen upotrebi u liječenju boli, raka, upale, neurodegenerativne bolesti ili infekcije organizmom Typanosoma cruzi kod sisavca.21. Compound of Formula I according to any one of patent claims 1 to 19, or its pharmaceutically acceptable salt, characterized in that it is intended for use in the treatment of pain, cancer, inflammation, neurodegenerative disease or infection with the organism Typanosoma cruzi in mammals. 22. Spoj Formule I u skladu s bilo kojim od patentnih zahtjeva 1 do 19, ili njegova farmaceutski prihvatljiva sol, naznačen time što je namijenjen upotrebi u liječenju osteolitičke bolesti kod sisavca.22. A compound of Formula I according to any of claims 1 to 19, or a pharmaceutically acceptable salt thereof, characterized in that it is intended for use in the treatment of osteolytic disease in a mammal. 23. Postupak dobivanja spoja u skladu s patentnim zahtjevom 1, naznačen time što se sastoji u: (a) za spoj Formule I, gdje je R2 NRbRc, reakciji odgovarajućeg spoja Formule II [image] sa spojem formule HNRbRc, u prisutnosti kondenzacijskog sredstva; ili (b) za spoj Formule I, gdje je R2 NRbRc, a Rb je H, reakciji odgovarajućeg spoja Formule II sa spojem formule O=C=N-Rc; ili (c) za spoj Formule I, gdje je R2 hetAr2 ili fenilni prsten izborno supstituiran s NHSO2(1-4C alkilom), reakciji odgovarajućeg spoja Formule II s odgovarajućim spojem formule HOC(=O)R2, u prisutnosti kondenzacijskog sredstva i baze; ili (d) za spoj Formule I, gdje je R2 (1-4C)alkil, (1-4C)fluoralkil, CF3, (1-4C)hidroksialkil ili (3-6C)cikloalkil, izborno supstituiran s (1-4C alkilom), CN, OH, CF3, CO2(1-4C alkilom) ili CO2H, reakciji odgovarajućeg spoja Formule II s odgovarajućim spojem formule (R2CO)2O, u prisutnosti baze; i izbornom uklanjanju ili dodavanju bilo koje zaštitne skupine i izbornom formiranju soli.23. The process of obtaining a compound in accordance with patent claim 1, characterized in that it consists in: (a) for a compound of Formula I, where R2 is NRbRc, to the reaction of the corresponding compound of Formula II [image] with a compound of the formula HNRbRc, in the presence of a condensing agent; or (b) for a compound of Formula I, where R2 is NRbRc, and Rb is H, to the reaction of the corresponding compound of Formula II with a compound of the formula O=C=N-Rc; or (c) for a compound of Formula I, where R 2 is hetAr 2 or a phenyl ring optionally substituted with NHSO 2 (1-4C alkyl), reacting the corresponding compound of Formula II with the corresponding compound of formula HOC(=O)R 2 , in the presence of a condensing agent and a base; or (d) for a compound of Formula I, where R2 is (1-4C)alkyl, (1-4C)fluoroalkyl, CF3, (1-4C)hydroxyalkyl or (3-6C)cycloalkyl, optionally substituted with (1-4C)alkyl , CN, OH, CF3, CO2(1-4C alkyl) or CO2H, to the reaction of the corresponding compound of Formula II with the corresponding compound of formula (R2CO)2O, in the presence of a base; and optional removal or addition of any protecting group and optional salt formation.
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